The goals of this project are to elucidate the mechanisms of action of tumor viruses and to determine the cellular alterations responsible for naturally occurring malignancies. Topics of present interest include: (1) transforming genes of retroviruses and cancer cells: (2) the biology of endogenous retroviruses: (3) the molecular biology of retrovirus replication and transformation: and (4) the application of knowledge gained from these studies to the search for the causes and mechanisms involved in human neoplastic transformation. Some of the highlights of the past year include: (1) The epidermal growth factor receptor (EGFR) gene was found to be frequently amplified and/or overexpressed in human malignancies. High levels of EGFR expression, which conferred a transformed phenotype to NIH/3T3 cells in the presence of ligand, were demonstrated in human tumor cell lines that contained amplified copies of the EGFR gene. (2) The human erbB-2 gene can be activated as an oncogene by its overexpression in NIH/3T3 cells. The high levels of the erbB-2 product associated with malignant transformation of NIH/3T3 cells were observed in human mammary tumor cells that overexpressed this gene. These findings demonstrate a new mechanism for acquisition of oncogenic properties by genes encoding growth factor receptor- like proteins. (3) The p21 proteins encoded by ras genes may act as regulatory proteins in the transduction of signals that lead to DNA synthesis. (4) The dbl transforming gene product, isolated from a human B-cell lymphoma, was demonstrated to be distinct among known transforming gene products. (4) The mechanism of action of the dideoxynucleosides, which markedly inhibit lentivirus infectivity, was further characterized.